Hematological malignancies display a spectrum of phenotypes. At one end is acute leukemia, characterized by proliferation of a population of cells blocked in their differentiation. Myelodysplasia is characterized by blocked differentiation and intramedullary cell death, leading to pancytopenia. In contrast, the myeloproliferative disorders (MPD) are characterized by an excess of well-differentiated cells. Chronic myelogenous leukemia, the archetypal MPD, is associated with the constitutively activated BCR-ABL tyrosine kinase that is specifically targeted by Imatimib. There are a spectrum of MPD represented by aberrant accumulation of each of the respective components of terminally differentiated myeloid lineage cells. These include CML, chronic myelomonocytic leukemia (CMML), agnogenic myeloid metaplasia (AMM) polycythemia vera (PV), essential thrombocythemia (ET), hypereosinophilic syndrome (HES), and systemic mast cell disease (SMCD). The genetic basis for several of these is known, and in each instance the respective MPD is caused by a constitutively activated tyrosine kinase. Examples include the TEL-PDGFRB fusion in CMML, the FIP1L1-PDGFRA fusion in HES, and KIT D816X mutations in SMCD. These genetic observations have important therapeutic consequences in that, for examples, the PDGFRA and PDGFRB rearranged MPD are effectively treated with imatinib. Although progress has been made, the genetic basis of the most prevalent among these, PV, ET and AMM, is not known. However, based on insights gained thus far, it seems plausible that these diseases might also be caused by mutations that constitutively activate tyrosine kinases. We hypothesized that is Polycythemia vera (PV), a MPD characterized by accumulation of erythrocytes and the presence of erythropoietin independent hematopoietic progenitor cells is caused by a mutation in the signal transduction machinery of the cell. Our preliminary data indicate that this indeed is the case, with a putative activating mutation of the JAK2 tyrosine kinase found in a majority of PV, as well as a significant fraction of ET and AMM, patients. Furthermore we hypothesize that these signaling abnormalities lead to alteration in gene expression in the hematopoietic progenitor cell that phenocopies erythropoietin stimulation. Therefore our specific aims will be: 1) Search the "kinome" in MPD patients to for mutations in signal transduction cascades 2) Array CGH screens for 5' activating deletions and/or amplification in the tyrosine kinome and other genetic changes in MPD 3) Determine the genetic consequences of signaling mutations in MPD cells through microarray profiling comparing normal and MPD specimens and MPD specimens harboring kinase mutations and 4) Validate Aberrant kinases as possible therapeutic targets in cell culture and murine models.